(3-methyl-5-carboxy-2-pentenyl)quinones

ABSTRACT

The present invention relates to (3-methyl-5 carboxy-2-pentenyl) quinones, lower alkyl esters and pharmaceutically acceptable salts thereof. The compunds are useful as anti-inflammatory agents.

United States Patent 1 Morimoto et al.

Apr. 17, 1973 (3-METHYL-5-CARBOXY-2- PENTENYL)QUINONES Inventors: Hiroshi Morimoto, Hyogo; Masazumi Watanabe; Isuke lmada, both of Appl. N0.: 113,773

Foreign Application Priority Data Feb. 7, 1970 Japan ..45/10846 Feb. 11, 1970 Japan ..45/11616 US. Cl ..260/396 R, 260/473 F, 260/473 S,

260/484 A, 260/484 R, 260/486 H, 260/488 H, 260/491, 260/520, 260/521 R, 260/535 R, 260/602, 424/305, 424/316, 424/317 51 1m.c|. ..C07c 61/36, C070 69/74 References Cited UNITED STATES PATENTS Primary Examiner-Vivian Garner Att0meyWenderoth, Lind & Ponack ABSTRACT The present invention relates to (3-methyl-5 carboxy- Z-pentenyl) quinones, lower alkyl esters and pharmaceutically acceptable salts thereof. The compunds v are useful as anti-inflammatory agents.

10 Claims, No Drawings Field of Search ..260/396 R 4/1946 Fieseret a1. ..260/396R 1 (Ii-METHYL-S-CARBOXY-Z- PENTENYIJQUINONES The present invention relates to novel (3-methyl-5- carboxy-Z-pentenyl)quinones. More concretely, the present invention provides a quinone derivative of the general formula (I):

' CH3 X CHzCH= CH1 CHzCOOH wherein each of X and X is independently methyl or methoxy, or alternatively X and X, taken together, represent -CI-l=CHCl-I=CH; its lower alkyl ester, and its pharmaceutically acceptable salt.

It has been unexpectedly found by the present inventors that the new quinone derivatives have strong antiinflammatory activity.

Therefore it is the main object of the present invention to provide new compounds which are useful as medicines.

Further, there is provided according to the present invention an industrially feasible method for the production of the above mentioned quinone derivatives, which comprises the first step of condensation reaction between a hydroquinone compound of the general formula (II):

'(wherein each of X and X has the same meaning as group) and the second step of oxidation reaction of thus obtained condensate of the general formula (IV).

The-lower alkyl group represented by Y and Y or that of end product lower alkyl ester may be substituted by a cycloalkyl group making at most 7 carbon atoms in total and is exemplified by methyl, ethyl, n-propyl, i-

. propyl, n-butyl, i-butyl, s-butyl,- t-butyl, n-pentyl, n-

according to per-se known means, for example as foldefined above) and a 4-hexenoic compound of the general formula (Ill ZCH1CH=JICHzCHrCOOY (111.)

(wherein Z is hydroxy, acetoxy or halogen, and Y is hydrogen or a lower alkyl group or a S-hexenoic compound of the general formula (1H,):

x" -cmcn=oomcmoooy II (IV) (wherein each of X, X has the same meaning as defined above and Y is hydrogen or a lower alkyl ,an alkyl iodide.

lows. The compound of the general formula (V):

(wherein Z is hydroxy or acetoxy) is produced from geranyl acetate according to per se known means (e.g.

ozonization), the compound (V) is oxidized with an oxidizing agent (e.g., air, silver oxide orthe like) in a suitable solvent (e.g. Iether, petroleum ether, hexane,

methanol or the like) at room temperature and if v desired the oxidation product is esterified, for example, with diazomethane to obtain a 4-hexenoic; compound of the general formula (VI):

CH3 z -omcrr=o-omorncoow (v1 (wherein Z is hydroxy or acetoxy and Y has the same. meaning as defined above). I y g A compound of the generalformula (VII):

cH;o- JoH1cHoooY= H (VII) (wherein Y has the same meaning as defined above) is reduced, for example, by a catalytic reduction .using a palladium catalyst (e.g. Pd/CaCQ at a temperature ranging from 15C to 30C to producea corresponding S-hexenoic compoundofthe general formula (VIII):

om=0H-oorr=omoooY H (VIII) (wherein Y has the same meaning as defined above), and of course the compound (VIII) wherein Y is hydrogen may be converted into the corresponding lower alkyl ester by an esterification, for example, with The compound (Ill or (IIl,,) wherein Z or Z' is halogen is prepared according to per se known means, for example, by halogenating the compound '(Vl) wherein Z is hydroxy and Y is a, lower'alkyl group or the compound (VlII)'wherein Y is a lower alkyl group with a halogenating agent (e.g. phosphorus tribromide,

phosphorus trichloride or the like).

In accordance with themethod of the present invention, the novel compound (I) is produced by reactions in the following schema agent is exemplified by ferric chloride, manganese dioxide, silver oxide, air and other mild oxidizing agents. The reaction is usually carried out in a suitable inert solvent, which is exemplified by ether, petroleum ether, hexane, methanol, ethanol or the like. The reaction is satisfactorily carried out at room temperature. After the reaction, the desired compound is easily recovered from the reaction mixture according to the per se known means (e.g., concentration,-extraction, chromatography, Crystallization or-the like). It is to be noted that when Y in the any of formulas 111, and (M1,) or Y in the formula IV is hydrogen, after the condensation reaction or after the oxidation tion, and thatwhen Y of thus obtained compound (I" is hydrogen, the compound may be converted by per se known means into a pharmaceutically acceptable salt such as a metal salt (e.g. potassium salt, sodium salt,

- magnesium salt, calcium salt or the like, or amine salt CH3 CH Z CHiCH=AI CHnCHzC O OY -l-. IL)

CH: CHi=CHJJCHiCH|C OOY (IIIs) loondensatlon 0H X CH3 CH3 X CHiCH=(JOHCH COOY l oxidation X CH3 X CHiCH=( JCH:CHiC O OY employed for the condensation of a phenol compound with an alcohol are conveniently employable in the reactionuof this invention. When Z in the, general formula (III.,) represents hydroxy or acetoxy or when 2' in the general formula (III,) is hydroxy, as the condensing agent are preferably employed an acid catalyst (e.g. boron trifluoride, zinc chloride or the like) and a sulfinyl, compound (e.g., p-nitrosulfinyl aniline, N-sulfinylp'-aminobenzoic acid ethyl ester or the like). When Z in the general formula (III,,) or Z in the general formula (lII ,)is halogen, it is recommended to use a metal catalyst (e.g., copper, tin, palladium, etc.) or an amalgamated metal (the metal component to be amalgamated being copper, tin, palladium, zinc, etc.). The condensation reaction is usually performed in a suitable inert solvent (e.g., ether, tetrahydrofuran, dioxane or'the like). The reaction is satisfactorily effected at a temperature ranging from l0C to 70C, and the reaction is usually completed in a period ranging from 2 to 10 hours and if desired the reaction time may be shortened by heating the reaction system. After the reaction, the produced condensate (IV) can be isolated according to per se known means (e.g. extraction), but the reaction product (IV) is usually employed asthe starting material for the next oxidation reaction without isolation from the reaction mixture.

The oxidation reaction is usually effected by treating thus formed compound (IV) with an oxidizing agent. In this reaction employable is any known oxidizing agent which has been employed for an oxidation of hydroquinone to benzoquinone, and such an oxidizing (e.g. dimethylamine salt, diethylamine salt or the like). These compounds are usually obtained as a mixture of trans-isomer and cis-isomer, andthe mixture may be, separated by per se known means (e.g. recrystalliza-, tion, chromatography or the like) into respective I isomers, and respective isomers as well as their mixture thereof should be included in-the scope of the present invention. 7 v Y When thus obtained compounds are employed as anti-inflammatories, the compounds are. usually administered orally in an amount ranging from 25 milligrams to 800 milligrams perjday for an adult.

In addition, it is to be noted that 2,3 ,S-trimethyl-G-(S I biological activity are the compounds wherein each of X and X is methyl or X and X, taken together represent CH=CI7l-CH=CI-I The following examples will serve to illustrate presentinvention with no intention of limiting the present invention thereto. In these examples, the parts by weight bear the same relationship to the parts by volume as do grams to millilitres.

EXAMPLE 1 l. 40 parts by weight of geran'yl acetate is dissolved into 300 parts by volume of methanol. Through the solution is passed at 78C one equivalent of ozone to produce the corresponding ozonide. Thus formed ozonide is decomposed by the addition of 20 parts by volume of dimethyl sulfide. The methanol is evaporated under reduced pressure and the residue is distilled under reduced pressure to obtain 19 parts by weight of 6acetoxy-4-methyl-4-hexenal, boiling at 80 to 85C/0.4 mml-lg as pale yellow oil.

IR v cm- 2720, 1730(CHO), 1730, 1235 (OCOCH l670(c=c).

2. 0.1 part by weight of 6-acetoxy-4-methyl-4-hexenal is dissolved into 5 parts by weight of 90 percent aqueous tetrahydrofuran. To the solution is added 0.4 part by weight of argentic oxide (AgO), and the mixture is stirred for 6 hours. The excess of argentic oxide and the precipitated silver metal are collected by filtration, and washed with boiling water. The filtrate and the washings are combined, made acidic by the addition of hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried with anhydrous sodium sulfate and concentrated by the evaporation of the solvent to obtain 0.083 part by weight of 6-acetoxy-4-methyl-4-hexenoic acid as colorless oil.

IR v cm" 2650"'"", 1710(COOH), NMR (in CCl.,) 1 value: 8.28(=CCH singlet), 8.04(COCH singlet), 7.62(COCH =CCH broad), 5.53(OCH doublet), 4.69(=CH, triplet), 0.71 (COOH, broad) Elementary analysis for C l-1 0.,

Calcd.: C, 58.05; H, 7.58 Found: C, 57.76; H, 7.69

3. 0.2 part by weight of 6acetoxy-4-methyL4-hexenoic acid is dissolved into 2 parts by volume of ethanol, followed by the addition of a solution of 0.18 part by weight of potassium hydroxide in 1 part by volume of 90 percent aqueous ethanol under stirring and cooling with ice. The reaction mixture is further stirred for 1 hour and to the reaction mixture is added water, followed by the addition of a dilute hydrochloric acid so as to make the reaction mixture acidic. The acidic mixture is extracted with ethyl acetate. The extract is washed with water, dried with anhydrous sodium sulfate and concentrated by the evaporation of the solvent to obtain 0.15 part by, weight of 6-hydroxy-4- methyl-4-hexenoic acid as pale yellow oil. The yield is 97 percent.

IR m cm 3350(OH), 2650""", 1710 (COOH), l680(c=c) NMR(in CDCl;,) 1 value: 8.32 (=CCH singlet), 7.6l(CH,COO, =CCH multiplet), 5.87(OCH doublet), 4.60(=CH, triplet), 3.37(COOH, OH, broad).

4. 0.192 part by weight of 6-hydroxy-4-methy1-4- hexenoic acid is esterified by the use of diazomethane to obtain 0.207 part by weight of methyl 6-hydroxy-4- methyl-4-hexenoate as colorless oil. The yield is 98 percent.

IR v cm 3400(OH), 1740, 1l65(COOCH NMR(in CCl,) 1' value: 8.38 (=CCH singlet), 7.70 (CH COO, =CCH multiplet), 6.67 (OH, singlet), 6.43 (COOCH singlet), 6.04(OCH doublet), 4.71 (=CH, triplet).

Elementary analysis for C H O Calcd.: C, 60.74; H, 8.92 Found: C, 60.55; H, 9.05

EXAMPLE 2 l. 2.2 parts by weight of silver oxide is added into 5 parts by weight of a 10 percent (weight/volume) of aqueous sodium hydroxide solution. To the reaction. mixture is added a solution of 1.6 parts by weight of 6- acetoxy-4-methyl-4-hexenal in 10 parts by weight of methanol under stirring, followed by stirring the resulting mixture for further 1 hour at 20C. 0.99 part by weight of 6-hydroxy-4-methyl-4hexenoic acid is obtained from the reaction mixture according to the same procedure as in Example 1(2). The yield is 76 percent.

2. 0.1 part by weight of methyl 6-hydroxy-4-methyl-4 hexanoate is dissolved into a mixture of 0.1 part by volume of petroleum ether, 015 part by volume of ether and 0.05 part by volume of pyridine. To the resultant solution is added 0.05 part by volume of phosphorus tribromide dissolved in petroleum ether, and the mixture is stirred at 0C for 2 hours. The reaction mixture is poured into water and the mixture is extracted with ether. The ethereal extract is washed with water, dried over anhydrous sodium sulfate and concentrated by the evaporation of ether to obtain methyl 6-brom-4methyl-4-hexenoate as pale yellow oil.

NMR (in CDCl,) rvalue: 8.27 (=CCH3, singlet),

7.60(=CCH CH COO, singlet), 6.36(COOCH singlet), 6.80(BrCH- doublet), 4.50(%H, triplet).

Mass Spectrum (m/e): 191(molecular peak OCH +2), 189(molecular peak. OCl-l 141(molecular peak Br), (molecular peak HBr).

EXAMPLE3 0.02 part by weight of ferric nitrate is added into 43 parts by volume of liquid ammonia, followed by the ad'- dition of 3.3 parts by weight of metallic sodium. Then acetylene gas is passed through the mixture solution at 50C, until the color of the mixture turns from gray colored into black colored, followed by the addition of 8.3 parts by weights of levulinic acid. The reaction mixture is stood at room temperature to evaporate ammonia and the residue is diluted with water. i

The mixture is made acidic by the addition of a dilute hydrochloric acid and thus formed y-ethynyl-y-hydroxyvaleric acid is extracted with ether, followed by the addition of diazomethane to obtain 'y-ethynyl-yhydroxyvaleric acid methyl ester. Ether is evaporated and the residue is dissolved into a 30 percent methanol aqueous solution. To the solution is added a suspension made from 0.5 part by weight of 5 percent palladiumbarium sulfate, 0.5 part by weight of quinoline and 20 parts by volume of methanol. Through the resultant mixture is passed hydrogen gass under shaking until an equimolar amount of hydrogen gas is consumed. The catalyst is filtered off and methanol is removed under a reduced pressure. The residue is dissolved into ether,

washed with a dilute hydrochloric acid to remove the remaining quinoline and dried with anhydrous sodium sulfate. The ether solution is concentrated by the evaporation of ether to obtain 7.8 parts by weight of 'yvinyl-'y-hydroxyvaleric acid methyl ester 1R u cm 3500(OH), 1730, 1200(COOCH l640(c=c) NMR(in 'CCl.,) r value: 8.75(CH -,-C-O),

8.20(CH c-o., 7.67(CH COO), 7.36(OH), 6.40(COOCH 5.00, 4.90 (CH 4. l 7(CH=) EXAMPLE 4 EXAMPLE 1 0.1 part by weight of 2,3-dimethoxy-5-methyl-l ,4- benzohydroquinone and 0.087 part by weight of methyl 6-hydroxy-4-methyl-4-hexanoate are dissolved into 5 parts by volume of dioxane. To the solution is added 0.3 part by volume of a 47 percent boron trifluoride .of ferric chloride in 15 parts by volume of methanol,

and the resultant mixture is shaken. The ethereal layer is separated, washed with water and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to obtain 0.15 part by weight of red oil. The oil is separated into two substances by column chromatography using silica gel. Firstly, 0.015 part by weight of the raw material 2,3-'dimethoxy-5- methyl-1,4-benzoquinone is recovered and then 0.067 part by weight of trans, cis-2,3-dimethoxy-5-methyl-6- (3-methyl-5-methoxycarbonyl-2-pentenyl)-1,4- benzoquinone is obtained.

UV A mp. (E oxidation .form 275 (449), reduction form 292 121 [R v,,,,,, cm- 1750, 1270, 1200(COOCl-l 1660,

1650, 1615(quinone) NMR(in CCl,) 1' value: 8.34 (cis=CCH singlet),

'8.28(trans=CH singlet), 8.08(Cl-l on the benzene ring, singlet), 8.04 (Cl-l on the benzene ring, singlet), 7.70 (trans=CCl-l,, Cl-l,COO, broad), 7.61 (cis=CCl-l,, broad), 6.90(CH on the benzene ring, doublet), 6.48 (trans COOCl-l singlet), 6.38 (cis COOCl-l singlet), 6.08(2 H CO, singlet), 5.08 (=CH, triplet) Mass Spectrum (m/e): 322(molecular peak), 307 (molecular. peak-CH 291(molecular peak- OCl-l 275, 247, 235, 197

Elementary analysis for C H O,

Calcd.: C, 63.34; H, 6.88 Found: C, 63.41; H, 6.75 2. 0.02 part by weight of trans, cis-2,3-dimethoxy-5- methyl-6-(3-methyl-5-methoxycarbonyl-2-pentenyl)- 1,4-benzoquinone and 0.2 part by weight of pyrogallol are dissolved into 2 parts by volume of methanol, followed by the addition of 2 parts by volume of a 10 percent methanolic potassium hydroxide solution. The resultant mixture is heated at 70C for 1 hour in a cur- 6 rent of nitrogen gas. Then, to the reaction mixture 18 added ice water, making the mixture acidic by the addition of a dilut hydrochloric acid and extracted with ether. The ether extract is washed with water, followed by the addition of a solution of 1 part by weight offerric chloride in 10, parts by volume of a 30 percentaqueous methanol, and the mixture is shaken. The ethereal layer is separated, washed with water and dried with anhydrous sodium sulfate. Ether is evaporated and the residue is purified by a column chromatography using silica gel as adsorbent and a mixture solvent of chloroform and ethanol (9:1) as elute to obtain 0.01 part by weight of trans, cis-2,3-dimethoxy-5-methyl-6- (5-carboxy-3-methyl-2-pentenyl l ,4-benzoquinone as red oil.

UV A f mp: oxidation form 275, reduction form- IR v,,,,,,,""4 em" 2650""""', 1700(COOl-l), 1660,

1650, 1610(quinone) NMR(in CCl,) 1- value: 8.3S(ClS=CCH singlet), 8.27(trans=Cl-l singlet), 8.09 (Cl-l5, on benzene ring, singlet), 7.72(cis=CCl-l Cl-l COO, broad), 7.60 (trans=CCl-l- CH COO, broad), 6.92(Cl-l on benzene ring, doublet), 6.l2(Cl-l O, singlet), 5.06(=Cl-l, triplet), --0.06(COOH, broad) Mass spectrum (m/e): 308(molecular peak), 293,

Thus produced trans, cis-2,3-dimethoxy-5-n1ethyl-6 (5-carboxy-3-methyl-2-penteny1)-1,4-benzoquinone is recrystallized from ether-hexane to obtain trans-2,3-dimethoxy-5-methyL6-(5-carboxy-3 methyl-2-p'entenyl)-l ,4-benzoquinone melting at to C as orange crystals.

NMR(in CDCl;,) 1' value: 8.24(=CCH singlet), 8.00 (Cl-l on benzene ring, singlet), 7.64(=CCH,, CH COO, broad), 6.80 (Cl-l, on benzene ring, doublet), 6.03 (OCl-l singlet), 5.00(=Cl7l, triplet), 0.24(COOH, broad). 1

Elementary analysis for C H O,

Calcd.: C, 62.32; H, 6.54

Found:C,62.2l;l-l,6.6l I I 3. 0.1 part by weight'of 2,3-dimethoxy 5methyl+6- (5-carboxy-3-methyl-2 penteny1)-1,4-benzoquinone is dissolved into 10 parts by volume of 1.5N ethanolic hydrochloric acid and the solution is stood at 20Cfor 15 hours. The reaction mixture is poured into water and extracted with ether. The ethereal extract is washed with water, dried over anhydrous sodium sulfate and concentrated by the evaporation of the sol-v vent. The residue is purified by column chromatog-, raphy using silica gel to obtain 2,3-dimethoxy- 5- methyl-6-(5-ethoxycarbonyl-3-methyl-2-pentenyl)- 1,4-benzoquinone as red oil.

UV )t 275 mu.

1R v,,,,, ,.""3 cm" 1730, 1275(COOC H 1660,

1650, 1615(quinone) NMR(in CCl,) 1' value: 8.82 (Cl-l triplet), 8.27 (trans=CCl-l 8.08(CH;, on the benzene ring, singlet), 7.78( =CCl-l,, CH,COO, broad), 6.94(Cl-l, on the benzene ring, doublet), 6.l4(2 H CO, singlet), 6.04(Cl-l,OCO, quartet) Mass Spectrum (m/e): 336 (molecular peak).

EXAMPLE 6 v 1. 0.174 part by weight of 2-methyl-l,4- naphthohydroquinone is reacted with 0.158 part by weight of methyl 6-hydroxy-4-methyl-4-hexanoate by the same means as in Example 5(1). Thus obtained yellow oil is purified by column chromatography using silica gel as adsorbent and a mixture solvent of benzene and hexane (95:5) as elute to obtain 0.106 part by weight of trans, cis-2-methy1-3-(3-methyl-5-methoxycarbonyl-2-pentenyl)-1,4-naphthoquinone as pale yellow oil.

UV lt f mp. (E oxidation form 244(562),

248(574), 262(473), 270(508), 330(89); reduction form 245(1114), 271(190), 325(90), 334(90).

IR v cm" 1740, 1290(COOCH 1660, 1620 (quinone).

NMR(in CCl.,) 1' value: 8.36(cis=CC1-l singlet), 8.24 (trans =CCH singlet), 7.92(Cl-l on benzene ring, singlet), 7.75(cis=CH CH COO, singlet), 7.60trans=CCH CH COO, broad), 6.75(CH on benzene ring, doublet), 6.5l(trans form, COOCH singlet), 6.40 (cis form, COOCH singlet), 5.0l(=Cl-l, triplet) Elementary analysis as C H O Calcd.: C, 73.06; H, 6.45 Found: C, 72.93; H, 6.37

2. 0.1 part by weight of trans, cis-2-methyl-3-(3- methyl-S-methoxycarbonyl-Z-pentenyl)-1,4- naphthoquinone is hydrolyzed with 30 percent aqueous potassium hydroxyde solution in the presence of hydrosulfite and then oxidized with ferric chloride to obtain yellow crystals. The crystals are recrystallized from ether to obtain trans-2-methyl-3-(5-carboxy-3- methyl-2-pentenyl)-l ,4-naphthoquinone as yellow needles melting at 130 to 131.5C.

NMR (in CDCl 1' value: 8.23(=CCH singlet), 7.89 (CH on benzene ring, singlet), 7.70(=CCH CH COO, broad), 6.70(CH on benzene ring, doublet), 4.96 (=Cl-l. triplet), -0.20(COOH, broad).

Elementary analysis as C l'l 0,,

Calcd.: C, 72.46; H, 6.08 Found: C, 72.54; H, 6.00 The mother liquor of the recrystallization is concentrated to obtain crystals. The crystals are recrystallized from ether to obtain cis-2-methyl-3-(5-carboxy-3- methyl-2pentenyl)-l,4-naphthoquinone as crystals melting at 118 to 119C.

NMR (in CDCl 1' value: 8.30 (=CCH singlet), 7.80(CH on benzene ring, singlet), 7.45(=CCH CH COOH, singlet), 6.61(CH on benzene ring, doublet), 4.92 (=Cl-l, triplet).

Elementary analysis for C I-1, 0,,

Calcd: C, 72.46; H, 6.08 Found: C, 72.21; H, 6.00

EXAMPLE 7 1. 0.304 part by weight of 2,3,5-trimethyl-l,4- benzohydroquinone is reacted with 0.158 part by weight of methyl 6-l1ydroxy-4-methyl-4-hexenoate by the same means as in Example 5(1) to obtain 0.217 part by weight of trans, cis-2,3,5-trimethyl-6-(3- methy1-5-methoxycarbonyI-Z-pentenyl 1 ,4- benzoquinone as pale yellow oil.

UV A f m .t(E, oxidation form 260(612),

267 624); reduction form 288(97). 1R v cm": 1740, 1300 (COOCH 1640, 1620 (quinone) yellow NMR(in CCl.,) 1' value: 8.36 (cis=CCl-l singlet), 8.26(trans=Cl-l singlet), 8.04(CH on benzene ring, singlet), 7.74 (cis=CH- Cl-1- COO, broad), 7.60(trans=Cl'l Cl-l COO, broad), 6.9l(CH on benzene ring, doublet), 6.45(trans form COOCl-l singlet), 6.38 (cis form COOCH singlet), 5.06(=CI-l, triplet).

Elementary analysis for C I-1 0 Calcd.: C, 70.32; H, 7.64 Found: C, 70.36; H, 7.59

2. 0.063 part by weight of 2,3,5 trimethyl-6-(3- methyl- 5-methoxycarbonyl-Z-pentenyl)-l ,4-

benzoquinone and 0.5 part by weight of pyrogallol are dissolved into 1 part by volume of methanol, followed by the addition of 3 parts by volume of a 10 percent methanolic potassium hydroxide solution, and the mixture is refluxed for 5 hours in a current of nitrogen gas. The reaction mixture is made acidic by the addition of a dilute hydrochloric acid, and extracted with ether. The ethereal extract is washed with water, followed by the addition of a solution of 1 part by weight of ferric chloride in 10 parts by volume of a 30 percent aqueous methanol, and the resultant mixture is shaken. The ethereal layer is separated, washed with water and dried over anhydrous sodium sulfate. Ether is evaporated and the residue is purified by a column chromatography using silica gel as adsorbent and a mixture solvent of chloroform and ethanol (:5) as elute to obtain crystals of trans, cis-2,3,5-trirnethyl-6- (5-carboxy-3-methyl-2-pentenyl l ,4-benzoquinone. The crystals are recrystallized from ether-petroleum ether to obtain 0.032 part by weight of the desired compound.

The crystals are again recrystallized from etherpetroleum ether to obtain trans-2,3,5-trimethyl-6-(5 carboxy-3-methyl-2-pentenyl )-l ,4-benzoquinone as yellow needles melting at 103 to 104C.

1R v cm" 2650""'" 1710(COOl-l), 1640,

1630(quinone) NMR(in CDCI rvalue: 8.20 (=CCH singlet), 8.00 (Cl-l on benzene ring, singlet), 7.62 (=CCH CH COO, broad), 6.78 (CH on benzene ring, doublet), 4.99 (=CH, triplet), 0.75 (COOH, broad) Elementary analysis for C 13 0 Calcd: C, 69.54; H, 7.30 Found: C, 69.65; H, 7.18

The mother liquor obtained in the above recrystallization procedure is concentrated to obtain crystals, which are recrystallized from ether-petroleum ether to obtain cis-2,3,5-trimethyl-6-(5-carboxy-3-methyl-2- pentenyl)-1,4-benzoquinone as yellow plates melting at 102 to 104C.

NMR (in CDCl;,) 7 value: 8.30 (=CCH singlet), 8.00 (Cl-1 on benzene ring, singlet), 7.46(=CCH Cl-LCOO, singlet), 6.76(CH on benzene ring, doublet), 4.96 (=CH, triplet), -0.60(COOH, broad).

Elementary analysis for (1 1-1 0.,

Calcd: C, 69.54; H, 7.30 Found: C, 69.73; H, 7.62

EXAMPLE 8 1 part by weight of 2,3,5-trimethyl-l ,4- benzohydroquinone and 0.8 part by weight of methyl 4- hydroxy-4-methyl-5 hexenoate .are dissolved into 30 parts by volume of dioxane. To the mixture is added 2 parts by volume of 47 percent boron trifluoride etherate in parts by volume of dioxane, while the mixture is stirred in a current of nitrogen gas. The mixture is further stirred for 3 hours at 20C. The reaction mixture is poured into 50 parts by volume of water, and the mixture is extracted three times with 50 parts by volume each of ether. The ether extracts are washed (3:97), and a further elution with 500 parts by volume of a mixture of ether and hexane (8:92) gives 0.709 part by weight of trans, cis-2,3,5-trimethyl-6-(3- methyl-5 -methoxy-carbonyl-Z-pentenyl )-l ,4- benzoquinone as yellow oil.

EXAMPLE 9 1.8 parts by weight of 2,3-dimethoxy-5'methyl-l,4- benzohydroquinone and 1.6 parts by weight of methyl 4-hydroxy-4-methyl-S-hexenoate are dissolved in 30 parts by volume of dioxane. Then, to the mixture is added 2 parts by volume of 47 percent boron trifluoride etherate in a current of nitrogen gas, and the mixture is stirred for 5 hours at 20C. The reaction mixture ispoured into 50 parts by volume of water and is extracted three times with 5 0 parts by volume each of ether. The ether extracts arev washed with water and concentrated under reduced pressure. The residue is dissolvedjnto 10 parts by volume of ether, followed by the addition -of a 56 percent aqueous sodium hydrosulfite solution. To the mixture is added a 30 percent aqueous potassium hydroxide solution under cooling with ice, and the resultant mixture is stirred for 3 hours. The reaction mixture is poured into water and is extracted with ether. The ether extract is washed with water, followed by the addition of 10 parts by volume of a solution of ferric chloride in 50 percent aqueous methanol, and the resultant mixture is shaken. The

ether extract is separated, washed with ether and dried with anhydrous sodium sulfate. The solvent is evaporated to obtain 1.4 parts by weight of trans, cis- (llHs -CH1CH=CCHI CHICOOH wherein each of X and X is independently methyl or methoxy, or alternatively X and X, taken together, represent CH=CH CHH; corresponding lower alkyl esters, and pharmaceutically acceptable salts thereof.

2. A quinone derivative as claimed in claim 1, wherein each of X and X is methyl.

3. A quinone derivative as claimed in claim 1, wherein X and X, taken together, represent CH=CHCl-l=Cl-l.

4. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3,5-trimethyl-6-(3- methyl-5-methoxycarbonyl-2-pentenyl)-l ,4- benzoquinone.

5. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3,5-trimethyl-6-(5- carboxy-3-methyl-2-pentenyl l ,4-benz0quinone.

6. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3-dimethoxy-5- methyl-6-(3-methyl-5-methoxycarbonyl-2-pentenyl)- ,4-benzoquinone.

7. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3-dimethoxy-5- methyl-6-(5-carboxy-3-methyI-Z-pentenyl) l,4- benzoquirione.

8. A quinone derivative as claimed in .claim '1,

wherein the quinone derivative is 2-methyl-3-(3- methyl-5-methoxy-carbonyl-2-pentenyl)-l ,4- naphthoquinone. v

9. A quinone derivative as claimed in claim 1,

wherein the quinone derivative is 2 methyl-3-(5-car- 

2. A quinone derivative as claimed in claim 1, wherein each of X and X'' is methyl.
 3. A quinone derivative as claimed in claim 1, wherein X and X'', taken together, represent -CH CH-CH CH-.
 4. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3,5-trimethyl-6-(3-methyl-5-methoxycarbonyl-2-pentenyl)-1,4-benzoquinone.
 5. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3,5-trimethyl-6-(5-carboxy-3-methyl-2-pentenyl)-1,4-benzoquinone.
 6. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3-dimethoxy-5-methyl-6-(3-methyl-5-methoxycarbonyl-2-pentenyl)-1,4 -benzoquinone.
 7. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3-dimethoxy-5-methyl-6-(5-carboxy-3-methyl-2-pentenyl)-1,4-benzoquinone.
 8. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2-methyl-3-(3-methyl-5-methoxy-carbonyl-2-pentenyl)-1,4-naphthoquinone.
 9. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2-methyl-3-(5-carboxy-3-methyl-2-pentenyl)-1,4-naphthoquinone.
 10. A quinone derivative as claimed in claim 1, wherein the quinone derivative is 2,3-dimethoxy-5-methyl-6-(5-ethoxycarbonyl-3-methyl-2-pentenyl)-1,4 -benzoquinone. 